Benzyl-oxyalkyl and hydroxyalkyl



Patented Sept. 12, 1939 UNITED STATES PATENT OFFICE BENZYL-OXYALKYL AND ETHERS OF OINCHONA METHOD HYDROXYALKYL ALKALOIDS AND OF PREPARATION Courtland L. Butler, Alice G. Renfrew, and Leonard H. Gretchen, Pittsburgh, Pa... assignors to Mellon Institute of Industrial Research, a corporation of Pennsylvania.

No Drawing. Application April 26, 1937, Serial No, 139,002

8 Claims.

This invention consists in new compositions of matter, benzyl-oxyalkyl and hydroxyalkyl ethers of phenolic hydroxyl-group-containing cinchona alkaloids, and in new processes for the hydroXy-alkylation of these alkaloids. The method for the preparation of benzyl-oxyalkyl cinchona derivatives consists in alkylation of phenolic hydroxyl-group-containing cinchona alkaloids with benzy -oxyalkyl aromatic sulfonates 10 according to the equation CH1 C Hz O(H)R Ar=an aromatic radical k-CH=OH;, =OHOH or 0H9OHa 30 Hydroxyalkyl cinchona ethers are readily prepared irom such benzyl-oxyalkyl derivatives by hydrolyzing them in dilute mineral acid according to the equation- CHOH-CH CH2 CH2 50 These cinchona derivatives have valuable medicinal properties, and in particular, find application as antipneumococcic drugs. We have reason to believe that they are very low in toxicity, that they are free of the damaging eye effect 55 characteristic of some cinchona derivatives, and

that they are highly active against the pneumococcus both in vitro and in vivo.

EXAMPLE 1.-Allcylatzon of apocupreine with benzyl-omyethyl benzene sulfonate 5 EXAMPLE 2.--Allcylati0n of apocupreine with. benzyl-oxyethyl p-toluene sulfonate In a similar way 50 parts of apocupreine in the form of potassium salt are alkylated in a1- coholic solution with 48 parts of benzyl-oxyethyl p-toluene sulfonate and the product, benzyloxyethyl apocupreine, is separated and worked p.

EXAMPLE 3.-Preparation of beneyl-oxyethyl apocupreine from b-chloroethyl apocupreine B-chloroethyl apocupreine is prepared by alkylating the potassium salt of apocupreine with B-chloroethyl p-toluene sulfonate.

90 parts of B-chloroethyl apocupreine are digested in benzyl alcohol solution in which 6.5 parts of sodium has been dissolved. The reaction mixture is diluted with ether, and the solution is filtered from sodium chloride. The desired product, benzyl-oxyethyl apocupreine, is extracted from the ether solution with dilute sulfuric acid and worked up in the usual way.

EXAMPLE 4.-Premaration of benzyl-oasyethyl hydrocupreine 90 parts of hydrocupreine are converted to potassium salt in alcoholic solution and warmed for two hours with 88 parts of benzyl-oxyethyl ptoluene sulfonate. The desired product, benzyloxyethyl hydrocupreine, is separated and worked up.

EXAMPLE 5.Preparation of I-benayl-0mymropyl apocupreine 46 parts of apocupreine in the form of potassium salt are alkylated in alcoholic solution with 48 parts of P-benzyl-oxypropyl p-toluene sulfonate. The desired product, I-benzyl-oxypropyl apocupreine, is separated and worked up.

EXAMPLE 6.-Prepa.ration of I-Denzyloxy Z-propyl apocupreine Jr-methyl p-benzyloxyethyl apocupreine 62 parts of apocupreine in the form of potassium salt are alkylated in alcoholic solution with 64 parts of l-benzyloxy 2-propyl p-toluene sulfonate. The desired product,'1-benzyloxy 2-propyl apocupreine, is separated and worked up.

EXAMPLE 7.Preparation of hydroacyethyl apocupreine EXAMPLE 8.-Preparation of hydroxyethyl hydro- 7 cup reine In a similar way benzyl-oxyethyl hydrocupreine is hydrolyzed in dilute hydrochloric acid to hydroxyethyl hydrocupreine and the product is separated and worked up.

EXAMPLE 9.-Prepa ration of F-hydromypropyl apocupreine V H l benzyl-oxypropyl apocupreine is similarly hydrolyzed in dilute acid and the droxypropyl apocupreine; is worked up. EXAMPLE 10.-Prepara.tion of I-hydmary Z-propyl apocupreine (or-methyl 'p-hydrowyevhyl apocupreine) l-benzyloxy 2-propyl apocupreine (oz-methyl- ;S-benzyloxyethyl apocupreine) is similarly hym dilu y eh er c ee d d t e fbenzyl-oxyalkyl ether of a product, T-hyseparated and.

product, l-hydroxy 2-propy1 apocupreine, is separated and worked up.

We claim as our invention:

1. As a new composition of matter, a benzyloxyalkyl ether of a phenolic-hydroxyl-groupcontaining cinchona alkaloid.

2. The method herein described of preparing a cinchona alkaloid, which consists in alkylating a phenolic hydroxylgroup-containing cinchona alkaloid with a benzyl-oxyalkyl aromatic sulfonate.

3. As a new composition of matter, benzyloxyethyl apocupreine.

4. The method herein described of preparing benzyl-oxyethyl apocupreine which consists in alkylating apocupreine at the phenolic hydroxyl group with benzyl-oxyethyl aromatic sulfonate.

5. As a new composition of matter, r-benzyloxypropyl apocupreine, of the formula,

as specified.

6. The method herein described of preparing r-benzyl-oxypropyl apocupreine, which consists in alkylating apocupreine at the phenolic hydroxyl group with T-benzyl-oxypropyl p-toluene sulfonate, and separating the desired product.

'7. As a new composition of matter, l-benzyloxy 2-propyl apocupreine (or-methyl 5 benzyloxy-ethyl apocupreine) of the formula,-

as specified. V v I 8. The method herein described of preparing l-benzyloxy 2-propyl apocupreine (or-methyl benzyloxyethyl apocupreine), which consists in alkylating apocupreine at the phenolic hydroxyl group with l-benzyloxy 2-propyl p-toluene sulfonate (or-methyl ,S-benzyloxyethyl para-toluene sulfonate).

COURTLAND L. BUTLER.

ALICE G. RENFREW.

LEONARD H. CRETCHER. 

